Methods of preparing tertiary carbinamine compounds

ABSTRACT

The present invention relates to a method for the preparation of tertiary carbinamine compounds from diastereoselective allylation and crotylation of N-unsubstituted imines derived from ketones.

The present application claims the benefit of priority under 35 U.S.C.§119(e) from U.S. provisional patent application No. 60/828,288, filedOct. 5, 2006.

FIELD OF THE INVENTION

The present invention relates to a method for the preparation oftertiary carbinamine compounds, particularly the preparation of tertiarycarbinamine compounds, from diastereoselective allylation andcrotylation of N-unsubstituted imines derived from ketones.

BACKGROUND OF THE INVENTION

Research into the addition of allyl organometallics to carbonylcompounds and their derivatives continues to proceed unabated—aconsequence of the fact that the resulting homoallylic products haveproven to be valuable synthons [S. E. Denmark and N. G. Almstead, ModernCarbonyl Chemistry, ed. J. Otera, Wiley-VCH, Weinheim, 2000, ch. 10; Y.Yamamoto and N. Asao, Chem. Rev., 1993, 93, 2207; and W. R. Roush,Comprehensive Organic Synthesis, ed. B. M. Trost, I. Fleming and C. H.Heathcock, Pergamon, Oxford, 2nd edn., 1991, vol. 2, pp 1-53]. Themajority of the research, however, has focused on the addition of theseorganometallics to aldehydes. For example, the reaction of

has previously been described by Kobayashi et al. [M. Sugiura, K. Hiranoand S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 7182; S. Kobayashi, K.Hirano, M. Sugiura, Chem. Commun., 2005, 104].

Although to a lesser extent, there have been some recent examples ofallylation of ketones [L. F. Tietze, K. Schiemann, C. Wegner and C.Wulff, Chem. Eur. J., 1998, 4, 1862; S. Casolari, D. D'Addario and E.Tagliavini, Org. Lett., 1999, 1, 1061; R. Hamasaki, Y. Chounan, H.Horino and Y. Yamamoto, Tetrahedron Lett., 2000, 41, 9883; R. M. Kambleand V. K. Singh, Tetrahedron Lett., 2001, 42, 7525; J. G. Kim, K. M.Waltz, I. F. Garcia, D. Kwiatkowski and P. J. Walsh, J. Am. Chem. Soc.,2004, 126, 12580; T. R. Wu, L. Shen and J. M. Chong, Org. Lett., 2004,6, 2701; and Y.-C. Teo, J.-D. Goh and T.-P. Loh, Org. Lett., 2005, 7,2743]. Until recently, the expansion of the substrate scope to includeimines and their derivatives had received limited attention. Some recentexamples of the addition of allylorganometallics to aldimine derivativescan be found in the following references [C. Bellucci, P. G. Cozzi andA. Umani-Ronchi, Tetrahedron Lett., 1995, 36, 7289; H. Nakamura, K.Nakamura and Y. Yamamoto, J. Am. Chem. Soc., 1998, 120, 4242; F. Fang,M. Johannsen, S. Yao, N. Gathergood, R. G. Hazell and K. A. Jørgensen,J. Org. Chem., 1999, 64, 4844; T. Gastner, H. Ishitani, R. Akiyama andS. Kobayashi, Angew. Chem., Int. Ed., 2001, 40, 1896; H. C. Aspinall, J.S. Bissett, N. Greeves and D. Levin, Tetrahedron Lett., 2002, 43, 323;M. Sugiura, F. Robvieux and S. Kobayashi, Synlett, 2003, 1749; R. A.Fernandes and Y. Yamamoto, J. Org. Chem., 2004, 69, 735; S.-W. Li and R.A. Batey, Chem. Commun., 2004, 1382; I. Shibata, K. Nose, K. Sakamoto,M. Yasuda and A. Baba, J. Org. Chem., 2004, 69, 2185; and C. Ogawa, M.Sugiura and S. Kobayashi, Angew Chem., Int. Ed., 2004, 43, 6491]. As forthe addition of allylorganometallics to ketimine derivatives, somerecent examples have also been reported [C. Ogawa, M. Sugiura and S.Kobayashi, J. Org. Chem., 2002, 67, 5359; S. Yamasaki, K. Fujii, R.Wada, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2002, 124, 6536; R.Berger, K. Duff and J. L. Leighton, J. Am. Chem. Soc., 2004, 126, 5686;H. Ding and G. K. Friestad, Synthesis, 2004, 2216].

However, there is yet no known synthetic methodology for the preparationof tertiary carbinamine compounds through diastereoselective allylationand crotylation of N-unsubstituted ketimines. New methodologies to solvethe difficulties associated with making these valuable tertiarycarbinamine compounds will no doubt have a tremendous impact in organicsynthesis and in the chemical industry. New methodologies may alsoprovide a new class of tertiary carbinamine compounds that cannot beobtained using conventional protocols. For example, the recent report ofaminoallylation of aldehydes by Kobayshi and coworkers has already had atremendous impact in organic synthesis [M. Sugiura, K. Hirano and S.Kobayashi, J. Am. Chem. Soc., 2004, 126, 7182; S. Kobayashi, K. Hirano,M. Sugiura, Chem. Commun., 2005, 104].

SUMMARY OF THE INVENTION

A new method for the preparation of tertiary carbinamine compounds fromthe diastereoselective allylation and crotylation of in situ generatedN-unsubstituted ketimines has been developed. The method has been shownto provide the homoallylic amines in good to excellent yields throughsimple acid-base extraction. Also, the crotylation of N-unsubstitutedketimines has been shown to be highly diastereoselective.

Accordingly, the present invention relates to a method of preparing anamine of the formula Ia and/or Ib comprising reacting a compound offormula II with a compound of formula III:

whereinR¹ and R² are independently selected from C₁₋₂₀alkyl, C₁₋₂₀alkoxy,C₂₋₂₀alkenyl, C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl, aryloxy,heteroaryl and heteroaryloxy, all of which are optionally substitutedand one or more of the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl,C₃₋₂₀cycloalkyl and C₃₋₂₀cycloalkoxy is optionally replaced with aheteromoiety selected from O, S, N, NR¹⁰ and NR¹⁰R¹¹;orR¹ and R² are linked to form an optionally substituted monocyclic orpolycyclic ring system having 4 to 20 atoms including the carbonyl towhich R¹ and R² are bonded, and one or more of the carbons of the ringsystem is optionally replaced with a heteromoiety selected from O, S, N,NR¹⁰ and NR¹⁰R¹¹;R³ to R⁷ are independently selected from H, C₁₋₂₀alkyl, C₁₋₂₀alkoxy,C₂₋₂₀alkenyl, C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl, aryloxy,heteroaryl and heteroaryloxy, the latter 9 groups being optionallysubstituted and one or more of the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy,C₂₋₂₀alkenyl, C₃₋₂₀cycloalkyl and C₃₋₂₀cycloalkoxy, is optionallyreplaced with a heteromoiety selected from O, S, N, NR¹⁰ and NR¹⁰R¹¹;R⁸ and R⁹ are independently selected from H, C₁₋₂₀alkyl,C₃₋₂₀cycloalkyl, aryl and heteroaryl, the latter 4 groups beingoptionally substituted;orR⁸ and R⁹ are linked to form an optionally substituted monocyclic orpolycyclic ring system having 4 to 20 atoms, including the B and O atomsto which R⁸ and R⁹ are bonded;R¹⁰ and R¹¹ are independently selected from H, C₁₋₂₀alkyl,C₃₋₂₀cycloalkyl, aryl and heteroaryl, the latter 4 groups beingoptionally substituted,in the presence of ammonia NH₃ or an ammonia equivalent of the formulaNH₄ ⁺X⁻, wherein X is an anionic ligand.

Other features and advantages of the present invention will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating preferred embodiments of the invention aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

It has been demonstrated for the first time that tertiary carbinaminecompounds can be efficiently and effectively generated throughdiastereoselective allylation and crotylation of N-unsubstituted iminesthat are derived from a diverse range of ketones. The method has beenshown to be a simple three-component reaction of a ketone, excessammonia or ammonia salt and an allylorganometallic reagent.

Accordingly, the present invention relates to a method of preparing anamine of the formula Ia and/or Ib comprising reacting a compound offormula II with a compound of formula III:

whereinR¹ and R² are independently selected from C₁₋₂₀alkyl, C₁₋₂₀alkoxy,C₂₋₂₀alkenyl, C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl, aryloxy,heteroaryl and heteroaryloxy, all of which are optionally substitutedand one or more of the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl,C₃₋₂₀cycloalkyl and C₃₋₂₀cycloalkoxy, is optionally replaced with aheteromoiety selected from O, S, N, NR¹⁰ and NR¹⁰R¹¹;orR¹ and R² are linked to form an optionally substituted monocyclic orpolycyclic ring system having 4 to 20 atoms including the carbonyl towhich R¹ and R² are bonded, and one or more of the carbons of the ringsystem is optionally replaced with a heteromoiety selected from O, S, N,NR¹⁰ and NR¹⁰R¹¹;R³ to R⁷ are independently selected from H, C₁₋₂₀alkyl, C₁₋₂₀alkoxy,C₂₋₂₀alkenyl, C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl, aryloxy,heteroaryl and heteroaryloxy, the latter 9 groups being optionallysubstituted and one or more of the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy,C₂₋₂₀alkenyl, C₃₋₂₀cycloalkyl and C₃₋₂₀cycloalkoxy is optionallyreplaced with a heteromoiety selected from O, S, N, NR¹⁰ and NR¹⁰R¹¹;R⁸ and R⁹ are independently selected from H, C₁₋₂₀alkyl,C₃₋₂₀cycloalkyl, aryl and heteroaryl, the latter 4 groups beingoptionally substituted;orR⁸ and R⁹ are linked to form an optionally substituted monocyclic orpolycyclic ring system having 4 to 20 atoms, including the B and O atomsto which R⁸ and R⁹ are bonded;R¹⁰ and R¹¹ are independently selected from H, C₁₋₂₀alkyl,C₃₋₂₀cycloalkyl, aryl and heteroaryl, the latter 4 groups beingoptionally substituted,in the presence of ammonia NH₃ or an ammonia equivalent of the formulaNH₄ ⁺X⁻, wherein X is an anionic ligand.

The term “C_(1-n)alkyl” as used herein means straight and/or branchedchain alkyl groups containing from one to n carbon atoms and includes,depending on the identity of n, methyl, ethyl, propyl, isopropyl,t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,hexadecyl, octadecyl, icosyl and the like and wherein n is an integerrepresenting the maximum number of carbon atoms in the group.

The term “C_(3-n)cycloalkyl” as used herein means saturated cyclic orpolycyclic alkyl groups containing from three to n carbon atoms andincludes, depending on the identity of n, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, cyclododecyl, cyclohexadecyl, cyclooctadecyl,cycloicosyl, adamantyl and the like, and wherein n is an integerrepresenting the maximum number of carbon atoms in the group.

The term “C_(1-n)alkoxy” as used herein means straight and/or branchedchain alkoxy groups containing from one to n carbon atoms and includes,depending on the identity of n, methoxy, ethoxy, propyoxy, isopropyloxy,t-butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy,dodecoxy, hexadecoxy, octadecoxy, icosoxy and the like, and wherein n isan integer representing the maximum number of carbon atoms in the group.

The term “C_(3-n)cycloalkoxy” as used herein means saturated cyclic orpolycyclic alkyoxy groups containing from three to n carbon atoms andincludes, depending on the identity of n, cyclopropoxy, cyclobutoxy,cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy, cyclononoxy,cyclodecoxy, cycloundecoxy, cyclododecoxy, cyclohexadecoxy,cyclooctadecoxy, cycloicosoxy and the like, and wherein n is an integerrepresenting the maximum number of carbon atoms in the group.

The term “C_(2-n)alkenyl” as used herein means straight and/or branchedchain alkenyl groups containing from two to n carbon atoms and one tosix double bonds and includes, depending on the identity of n, vinyl,allyl, 1-butenyl, 2-hexenyl and the like, and wherein n is an integerrepresenting the maximum number of carbon atoms in the group.

The term “aryl” as used herein means a monocyclic or polycycliccarbocyclic ring system containing one or two aromatic rings and from 6to 14 carbon atoms and includes phenyl, naphthyl, anthraceneyl,1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl,indenyl and the like.

The term “heteroaryl” as used herein means mono- or polycyclicheteroaromatic radicals containing from 5 to 14 atoms, of which 1 to 4atoms are a heteroatom selected from nitrogen, oxygen and sulfur andincludes furanyl, thienyl, pyrrolo, pyridyl, indolo, benzofuranyl andthe like.

The term “halo” as used herein means halogen and includes chloro,fluoro, bromo and iodo.

The term “one or more” as used herein means that from one to the maximumallowable substitutions are allowed.

The present invention includes combinations of groups and substituentsthat are permitted and would provide a stable chemical entity accordingto standard chemical knowledge as would be known to those skilled in theart.

The term “polycyclic” or “ring system” as used herein means a cyclicgroup containing more than one ring in its structure, and includesbicyclic, tricyclic, bridged and spiro ring systems and the like.

It is an embodiment of the invention that the compounds of formulae Ia,Ib and II include those in which R¹ and R² are independently selectedfrom C₁₋₁₀alkyl, C₂₋₁₀alkenyl, aryl and heteroaryl, all of which areoptionally substituted. In a further embodiment of the invention, R¹ andR² in the compounds of the formulae Ia, Ib and II are independentlyselected from methyl, ethyl, propyl, butyl, pentyl, ethene, styrene,phenyl, benzyl, thiophene and indole, all of which are optionallysubstituted.

It is another embodiment of the invention that the compounds of formulaeIa, Ib and II include those in which R¹ and R² are linked to form anoptionally substituted monocyclic or polycyclic ring system having 6 to16 carbon atoms including the carbonyl to which R¹ and R² are bonded. Ina further embodiment of the invention, one or more of the carbons ofthis ring system is optionally replaced with a heteromoiety selectedfrom O, S, N, NR¹⁰ and NR¹⁰R¹¹, in which R¹⁰ and R¹¹ are independentlyselected from H, C₁₋₆alkyl and aryl. In a still further embodiment ofthe invention, R¹ and R² in the compounds of the formulae Ia, Ib and IIare linked to form a ring system selected from cyclohexane,bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene and fluorene, all ofwhich are optionally substituted, and/or one or more of the carbons ofcyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene or fluoreneis optionally replaced with a heteromoiety selected from O, S, N andNR¹⁰; in which R¹⁰ is H or benzyl.

In an embodiment of the invention, the optional substituents on R¹ andR² in the compounds of the formulae Ia, Ib and II are independentlyselected from OH, halo, CN, NO₂, phenyl, benzyl, OC₁₋₆alkoxy, C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkenyloxy, NH₂, NH(C₁₋₆alkyl),N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl,SO₂NH₂, SO₂NHC₁₋₆alkyl, and SC₁₋₄alkyl. More particularly, in anotherembodiment of the invention, the optional substituents on R¹ and R² inthe compounds of the formulae Ia, Ib and II are independently selectedfrom OH, F, Cl, Br, CN, NO₂, phenyl and C₁₋₄alkyl. Still moreparticularly, the optional substituents on R¹ and R² in the compounds ofthe formulae Ia, Ib and II further comprise at least one stereocenter.

It is an embodiment of the invention that R³ to R⁷ in the compounds ofthe formulae Ia, Ib and III are independently selected from H,C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, aryl and heteroaryl, the latter 4 groupsbeing optionally substituted. In another embodiment of the invention,one or more of the carbons in C₁₋₁₀alkyl and C₃₋₁₀cycloalkyl isoptionally replaced with a heteromoiety selected from O, S, N, NR¹⁰ andNR¹⁰R¹¹ in which R¹⁰ and R¹¹ are independently selected from H andC₁₋₆alkyl. In a particular embodiment of the invention, R³ to R⁷ in thecompounds of the formulae Ia, Ib and III are independently selected fromH and C₁₋₆alkyl. In a more particular embodiment of the invention, R³ toR⁷ in the compounds of the formulae Ia, Ib and III are independentlyselected from H and methyl. Still further, in an embodiment of theinvention, the optional substituents on R³ and R⁷ in the compounds ofthe formulae Ia, Ib and III are independently selected from OH, halo,CN, NO₂, phenyl, benzyl, OC₁₋₆alkoxy, C₁₋₆alkyl, C₁₋₆alkenyl,C₁₋₆alkenyloxy, NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl),C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl, andSC₁₋₄alkyl.

It is an embodiment of the invention that R³ and R⁹ in the compound ofthe formula III are independently selected from H, C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, aryl and heteroaryl, the latter 4 groups beingoptionally substituted. In a more particular embodiment of theinvention, R⁸ and R⁹ in the compound of the formula III areindependently selected from H or C₁₋₆alkyl. In another embodiment of theinvention, R⁸ and R⁹ in the compound of the formula III are linked toform an optionally substituted monocyclic or polycyclic ring systemhaving 5 to 12 atoms, including the B and O atoms to which R⁸ and R⁹ arebonded. In a more particular embodiment of the invention, R⁸ and R⁹ inthe compound of the formula III are linked to form an optionallysubstituted monocyclic or bicyclic ring system having 5 to 12 atoms,including the B and O atoms to which R⁸ and R⁹ are bonded. It is anembodiment of the invention that the optional substituents on R⁸ and R⁹in the compound of the formula III are independently selected from OH,halo, CN, NO₂, phenyl, benzyl, OC₁₋₆alkoxy, C₁₋₆alkyl, C₁₋₆alkenyl,C₁₋₆alkenyloxy, NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl),C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl, andSC₁₋₄alkyl. Still further, it is an embodiment of the invention that theoptional substituent on R⁸ and R⁹ in the compound of the formula III isC₁₋₄alkyl.

In an embodiment of the invention, the method is performed in thepresence of ammonia. In yet another embodiment of the invention, themethod is performed in the presence of an ammonia salt NH₃ ⁺X⁻ in whichX is an anionic ligand. In a further embodiment of the invention, X isselected from halo, R¹²COO, R¹²SO₄ and BF₄ in which R¹² is selected fromC₁₋₁₀alkyl, C₃₋₂₀cycloalkyl, aryl and heteroaryl, all of which areoptionally substituted. In an embodiment of the invention, X is selectedfrom Cl, Br, R¹²COO, R¹²SO₄ and BF₄ and in which R¹² is selected fromC₁₋₄alkyl, C₃₋₁₂cycloalkyl, aryl and heteroaryl, all of which areoptionally substituted. In a still further embodiment of the invention,the optional substituents on R¹² are independently selected from OH,halo, CN, NO₂, phenyl, benzyl, OC₁₋₆alkoxy, C₁₋₆alkyl, C₁₋₆alkenyl,C₁₋₆alkenyloxy, NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl),C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl, andSC₁₋₄alkyl.

In an embodiment of the invention, the method is performed in an inertorganic solvent. More particularly, the organic solvent is selected frommethanol, ethanol, propanol, butanol, toluene, tetrahydrofuran,acetonitrile, benzene, methylene chloride. Still more particularly, theorganic solvent is methanol.

Also within the scope of the invention, the method is performed at roomtemperature or above or below room temperature for example at atemperature of from −40° C. to 100° C., suitably 0° C. to 50° C. moresuitably 10° C. to 30° C. Suitably, the method is performed at roomtemperature. A person skilled in the art would appreciate that thereaction temperature may vary depending on a number of variables,including, but not limited to the structure of the starting materials(compounds of formulae II and III), the solvent, reaction pressure andthe choice of ammonia or ammonia equivalent. A person skilled in the artwould be able to optimize the reaction temperature to obtain the bestyields and overall performance of the reaction.

Although there are a number of methods which have been surveyed tosynthesize and isolate N-unsubstituted ketimines of the compound of theformula IV [P. L. Pickard and T. L. Tolbert, J. Org. Chem., 1961, 26,4886; D. R. Boyd, K. M. McCombe and N. D. Sharma, Tetrahedron Lett.,1982, 23, 2907; A. J. Bailey and B. R. James, Chem. Commun., 1996, 2343;Y. Bergman, P. Perlmutter and N. Thienthong, Green Chem., 2004, 6, 539;and R. W. Layer, Chem. Rev., 1963, 63, 489], the present inventors havefound that the three-component reaction of the ketone of the compound ofthe formula II, excess ammonia and the allylorganometallic of thecompound of the formula III was the most efficient and effectiveprotocol to generate the desired homoallylic amines of the compounds offormulae Ia and Ib (Scheme I).

While not wishing to be limited by theory, it is believed that theN-unsubstituted ketimine of the compound of formula IV is formed in situprior to its reaction with the allylorganometallic of the compound offormula III [M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem. Soc.,2004, 126, 7182; S. Kobayashi, K. Hirano, M. Sugiura, Chem. Commun.,2005, 104; B. Davis, J. Labelled Compd. Radiopharm., 1987, 24, 1221; andN. Haider, G. Heinisch, I. Kurzmann-Rauscher and M. Wolf, Liebigs Ann.Chem., 1985, 167]. The addition of a series of allyl organometallics tothe in situ generated ketimine of the compound of formula IV(R¹=4-BrC₆H₄, R²=Me) have been investigated.

The following non-limiting examples are illustrative of the presentinvention:

EXAMPLES Materials and Methods

All ketones in liquid form were distilled prior to use. All ketones insolid form were used as received. All other reagents were used asreceived (Aldrich, Acros, Strem). MeOH was dried over magnesiummethoxide and distilled prior to use. 2 M solutions of allyl, (E)- and(Z)-crotylboronic acid in anhydrous MeOH were prepared just prior to use(exact molarities were confirmed by titration with benzaldehyde) [H. C.Brown, U.S. Racherla and P. J. Pellechia, J. Org. Chem., 1990, 55,1868].

Melting points were uncorrected and were measured on a Fisher-Johnsmelting point apparatus. ¹H and ¹³C NMR were recorded at 300 or 500 MHzand 75 or 125 MHz respectively on a Bruker Spectrospin 300 or 500 MHzspectrometer. Proton chemical shifts were internally referenced to theresidual proton resonance in CDCl₃ (δ 7.26). Carbon chemical shifts wereinternally referenced to the deuterated solvent signals in CDCl₃ (δ77.00). Infrared spectra were obtained on a Bruker VECTOR22 FT-IRspectrometer. HRMS-Cl and HRMS-ESI were performed on a Waters/MicromassGCT time-of-flight mass spectrometer and a Waters/Micromass Q-TOF Globalquadrupole time-of-flight mass spectrometer respectively.

Example 1 General Procedure for the Allylation of N-Unsubstituted IminesDerived from Ketones

To the ketone (0.5 mmol) was added a solution of ammonia in methanol(ca. 7M in MeOH, 0.75 mL, ca. 10 equiv.). The resulting solution wasstirred for 15 min at rt. A freshly prepared solution of allylboronicacid (5e) (2M in MeOH, 0.4 ml, 0.8 mmol) was then added dropwise over 5min. The reaction mixture was subsequently stirred for 16 h at rt. Allvolatiles were removed in vacuo and the residue re-dissolved in Et₂O (15mL). The desired amine was then extracted with 1 N HCl (15 ml). Theacidic aqueous extract was washed with Et₂O (3×15 mL). The aqueousextract was next made alkaline by addition of solid NaOH (ca. 5 g). Thealkaline aqueous layer was then extracted with dichloromethane (3×15mL). The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo to afford the desired tertiary carbamine (6).

(i) 1-(4-Bromophenyl)-1-methylbut-3-enylamine (6a)

6a was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 500 MHz) δ7.44 (2H, d, J=8.5 Hz), 7.35 (2H, d, J=8.5 Hz), 5.55 (1H, dddd, J=18.0,9.5, 8.0, 7.0 Hz), 5.09-5.04 (2H, m), 2.53 (1H, dd, J=13.5, 7.0 Hz),2.38 (1H, dd, J=13.5, 8.0 Hz), 1.49 (2H, br s), 1.44 (3H, s); ¹³C NMR(CDCl₃, 125 MHz) δ 147.79, 133.89, 131.14, 127.26, 120.12, 118.81,54.45, 49.64, 30.93; IR (film)

3423, 1638 cm⁻¹; HRMS (Cl) m/z calcd. for C₁₁H₁₅BrN (MH⁺) 240.0388,found 240.0395.

(ii) 1,1-Diethylbut-3-enylamine (6b)

6b was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ5.77 (1H, ddt, J=16.0, 11.0, 7.5 Hz)), 5.04 (1H, d, J=11.0 Hz), 5.03(1H, d, J=16.0 Hz), 2.03 (2H, d, J=7.5 Hz), 1.32 (4H, q, J=7.5 Hz), 1.18(2H, br s), 0.81 (6H, t, J=7.5 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 134.44,117.69, 53.36, 43.85, 31.66, 7.70; IR (film) ν 3420, 1636 cm⁻¹; HRMS(ESI) m/z calcd. for C₈H₁₈N (MH⁺) 128.1439, found 128.1444.

(iii) 2-Amino-2-methylpent-4-en-1-ol (6c)

6c was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ5.79 (1H, ddt, J=16.5, 10.5, 7.5 Hz), 5.12-5.01 (2H, m), 3.30 (1H, d,J=10.5 Hz), 3.25 (1H, d, J=10.5 Hz), 2.45 (3H, br s), 2.11 (2H, d, J=7.5Hz), 1.01 (3H, s); ¹³C NMR (CDCl₃, 75 MHz) δ 133.77, 118.51, 68.07,52.70, 44.28, 24.53; IR (film) ν 0.3345, 3157, 1639 cm⁻¹; HRMS (Cl) m/zcalcd. for C₆H₁₄NO (MH⁺) 116.1075, found 116.1072.

(iv) 1-Benzyl-1-phenylbut-3-enylamine (6d)

6d was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ7.38-7.08 (8H, m), 6.90-6.84 (2H, m), 5.53 (1H, dddd, J=17.0, 10.0, 8.5,5.5 Hz), 5.15-5.00 (2H, m), 3.12 (1H, d, J=13.0 Hz), 2.97 (1H, d, J=13.0Hz), 2.86 (1H, dd, J=13.5, 5.5 Hz), 2.44 (1H, dd, J=13.5, 8.5 Hz), 1.50(2H, brs); ¹³C NMR (CDCl₃, 75 MHz) δ 146.52, 137.09, 134.08, 130.68,128.07, 127.86, 126.46, 126.30, 126.19, 118.81, 57.97, 50.54, 47.62; IR(film)

3401, 1677 cm⁻¹; HRMS (ESI) m/z calcd. for C₁₇H₂₀N (MH⁺) 238.1596, found238.1585.

(v) 1-Methyl-1-(3-methylbutyl)but-3-enylamine (6e)

6e was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ5.74 (1H, ddt, J=17.0, 10.0, 7.5 Hz), 5.05-4.93 (2H, m), 2.00 (2H, d,J=7.5 Hz), 1.40 (1H, septet, J=6.5 Hz), 1.29-1.20 (2H, m), 1.19-1.03(4H, m), 0.95 (3H, s), 0.80 (6H, d, J=6.5 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ134.50, 117.77, 51.14, 47.15, 40.36, 32.82, 28.45, 27.71, 22.53; IR(film)

3385, 1636 cm⁻¹; HRMS (ESI) m/z calcd. for C₁₀H₂₂N (MH⁺) 156.1752, found156.1745.

(vi) 1-Ethyl-1-(4-Methoxyphenyl)but-3-enylamine (6f)

6f was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 500 MHz) δ7.31 (2H, d, J=9.0 Hz), 6.86 (2H, d, J=9.0 Hz), 5.53 (1H, dddd, J=17.5,10.0, 8.5, 6.0 Hz), 5.06 (1H, d, J=17.5 Hz), 5.03 (1H, d, J=10.0 Hz),3.80 (3H, s), 2.59 (1H, dd, J=13.5, 6.0 Hz), 2.36 (1H, dd, J=13.5, 8.5Hz), 1.85 (1H, dq, J=14.0, 7.5 Hz), 1.66 (1H, dq, J=14.0, 7.5 Hz), 1.52(2H, br s), 0.71 (3H, t, J=7.5 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 157.72,138.66, 134.32, 126.93, 118.34, 113.27, 57.06, 55.16, 48.37, 36.05,8.04; IR (film)

3420, 1638, 1610, 1511, 1248 cm⁻¹; HRMS (Cl) m/z calcd. for C₁₃H₂₀NO(MH⁺) 206.1545, found 206.1565.

(vii) 4-(1-Amino-1-methylbut-3-enyl)benzonitrile (6g)

6g was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ7.57 (4H, apparent s), 5.55-5.40 (1H, m), 5.07-4.97 (2H, m), 2.51 (1H,dd, J=13.5, 6.5 Hz), 2.36 (1H, dd, J=13.5, 8.0 Hz), 1.46 (2H, br s),1.43 (3H, s); ¹³C NMR (CDCl₃, 75 MHz) δ 154.26, 133.32, 131.99, 126.36,119.37, 119.03, 110.05, 54.94, 49.50, 30.85; IR (film)

3499, 2228, 1639 cm⁻¹; HRMS (Cl) m/z calcd. for C₁₂H₁₅N₂ (MH⁺) 187.1235,found 187.1235.

(viii) 1-Methyl-1-(4-nitrophenyl)but-3-enylamine (6h)

6h was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 500 MHz) δ8.16 (2H, d, J=9.0 Hz), 7.66 (2H, d, J=9.0 Hz), 5.53 (1H, dddd, J=17.0,10.5, 8.0, 7.0 Hz), 5.07 (1H, d, J=10.5 Hz), 5.06 (1H, d, J=17.0 Hz),2.57 (1H, dd, J=13.5, 7.0 Hz), 2.42 (1H, dd, J=13.5, 8.0 Hz), 1.54 (2H,br s), 1.50 (3H, s); ¹³C NMR (CDCl₃, 125 MHz) δ 156.28, 146.47, 133.13,126.45, 123.30, 119.43, 55.01, 49.55, 30.92; IR (film) ν3375, 1639,1526, 1351 cm⁻¹; HRMS (Cl) m/z calcd. for C₁₁H₁₅N₂O₂ (MH⁺) 207.1134,found 207.1132.

(ix) 1-Methyl-1E-styrylbut-3-enylamine (6i)

6i was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ7.45-7.15 (5H, m), 6.46 (1H, d, J=16.0 Hz), 6.28 (1H, d, J=16.0 Hz),5.87-5.72 (1H, m), 5.18-5.05 (2H, m), 2.31 (1H, dd, J=16.5, 7.5 Hz),2.23 (1H, dd, J=16.5, 8.0 Hz), 1.41 (2H, br s), 1.27 (3H, s); ¹³C NMR(CDCl₃, 75 MHz) δ 138.42, 137.22, 133.95, 128.39, 128.27, 127.06,126.14, 118.45, 52.96, 48.00, 28.57; IR (film) ν 3545, 1638 cm⁻¹; HRMS(Cl) m/z calcd. for C₁₃H₁₈N (MH⁺) 118.1439, found 118.1449.

(x) 9-Allyl-9H-fluoren-9-ylamine (6j)

6j was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 500 MHz) δ7.66 (2H, d, J=7.5 Hz), 7.51 (2H, d, J=7.0 Hz), 7.38-7.30 (4H, m), 5.57(1H, ddt, J=17.0, 10.0, 7.5 Hz), 5.01 (1H, dd, J=17.0, 1.5 Hz), 4.96(1H, d, J=10.0 Hz), 2.70 (2H, d, J=7.5 Hz), 1.81 (2H, br s); ¹³C NMR(CDCl₃, 125 MHz) δ 150.86, 139.28, 133.22, 128.00, 127.53, 123.26,119.85, 118.60, 64.71, 45.46; IR (film) ν3360, 1640 cm⁻¹; HRMS (ESI) m/zcalcd. for C₁₆H₁₆N (MH⁺) 222.1283, found 222.1278.

(xi) 4-Allyl-1-benzylpiperidin-4-ylamine (6k)

6k was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 300 MHz) δ7.32-7.15 (5H, m), 5.81 (1H, ddt, J=17.0, 10.0, 7.5 Hz), 5.12-5.01 (2H,m), 3.48 (2H, s), 2.58-2.48 (2H, dq, J=12.0, 4.0 Hz), 2.30 (2H, dt,J=11.0, 3.0 Hz), 2.09 (2H, d, J=7.5 Hz), 1.61 (2H, ddd, J=13.0, 10.5,4.0 Hz), 1.41-1.31 (2H, m), 1.08 (2H, br s); ¹³C NMR (CDCl₃, 75 MHz) δ138.43, 133.51, 128.88, 127.95, 126.69, 118.29, 63.08, 49.39, 48.67,47.60, 37.83; IR (film) ν3422, 1639 cm⁻¹; HRMS (ESI) m/z calcd. forC₁₅H₂₃N₂ (MH⁺) 231.1861, found 231.1862.

(xii) 1-Phenyl-1-thiophen-2-ylbut-3-enylamine (6l)

6l was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 500 MHz) δ7.49 (2H, dt, J=7.5, 1.0 Hz), 7.33 (2H, t, J=8.0 Hz), 7.27-7.17 (2H, m),6.94 (1H, dd, J=5.0, 3.5 Hz), 6.90 (1H, dd, J=3.5, 1.0 Hz), 5.62 (1H,ddt, J=17.0, 10.0, 7.0 Hz), 5.19 (1H, d, J=17.0, 1.5 Hz), 5.13 (1H, ddd,J=10.0, 1.5, 1.0 Hz), 3.08 (1H, dd, J=14.0, 7.0 Hz), 3.01 (1H, dd,J=14.0, 7.5 Hz), 2.09 (2H, br s); ¹³C NMR (CDCl₃, 75 MHz) δ 154.78,147.10, 133.63, 128.15, 126.77, 126.50, 126.01, 124.22, 123.64, 119.55,59.32, 49.15; IR (film)

3410, 1639 cm⁻¹; HRMS (Cl) m/z calcd. for C₁₄H₁₆NS (MH⁺) 230.1003, found230.1017.

(xiii) 1-(1H-Indol-3-yl)-1-methylbut-3-enylamine (6m)

6m was isolated as a clear, colorless oil: ¹H NMR (CDCl₃, 500 MHz) δ8.03 (1H, br s), 7.84 (1H, d, J=8.0 Hz), 7.37 (1H, d, J=8.0 Hz), 7.19(1H, dt, J=7.5, 1.0 Hz), 7.12 (1H, dt, J=7.5, 1.0 Hz), 7.07 (1H, d,J=2.5 Hz), 5.65 (1H, ddt, J=17.5, 10.0, 7.5 Hz), 5.06 (1H, d, J=17.5Hz), 5.03 (1H, d, J=10.0 Hz), 2.79 (1H, dd, J=13.5, 7.5 Hz), 2.63 (1H,dd, J=13.5, 7.5 Hz), 1.85 (2H, br s), 1.61 (3H, s); ¹³C NMR (CDCl₃, 75MHz) δ 137.30, 134.93, 125.20, 124.74, 121.77, 120.91, 120.51, 119.21,117.92, 111.35, 52.39, 48.20, 30.00; IR (film)

3205, 1639 cm⁻¹.

(xiv) 1-Allyl-4-tert-butylcyclohexylamine (6n)

6n was isolated as a clear, colorless oil (d.r.=87:13). Thediastereomeric ratio was determined by ¹H NMR of the crude sample. Maindiastereomer: ¹H NMR (CDCl₃, 300 MHz) δ 5.83 (1H, ddt, J=17.0, 10.5, 7.5Hz), 5.08-4.98 (2H, m), 2.02 (2H, d, J=7.5 Hz), 1.60-1.40 (4H, m),1.34-1.00 (6H, m), 0.90-0.83 (1H, m), 0.83 (9H, s); ¹³C NMR (CDCl₃, 75MHz) δ 134.26, 117.87, 50.16, 49.94, 48.11, 38.43, 32.30, 27.50, 22.42;IR (film)

3368, 1638 cm⁻¹; HRMS (Cl) m/z calcd. for C₁₃H₂₆N (MH⁺) 196.2065, found196.2068. The stereochemistry of 6n (axial NH₂) was confirmed byconverting it (allylbromide, iPr₂NEt, CH₂Cl₂; 49%) to the previouslyknown compound N-Allyl-1-Allyl-4-tert-butylcyclohexylamine (axialNHCH₂CH═CH) [D. L. Wright, J. P. Schulte, II and M. A. Page, Org. Lett.,2000, 2, 1847].

(xv) 2-Allyl-bicyclo[2.2.1]hept-2-ylamine (6o)

6o was isolated as a clear, colorless oil (d.r.=94:6). Thediastereomeric ratio was determined by ¹H NMR of the crude sample. Maindiastereomer: ¹H NMR (CDCl₃, 300 MHz) δ 5.78 (1H, ddt, J=17.0, 10.5, 7.5Hz), 5.08-4.97 (2H, m), 2.10 (2H, d, J=7.5 Hz), 1.88 (1H, d, J=3.5 Hz),1.78 (1H, ddt, J=12.5, 9.0, 3.0 Hz), 1.60-1.42 (3H, m), 1.24-1.08 (6H,m), 0.82 (1H, dd, J=12.5, 3.0 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 134.57,117.95, 57.99, 47.41, 46.69, 46.48, 38.30, 37.54, 28.43, 22.92; IR(film)

3400, 1638 cm⁻¹; HRMS (Cl) m/z calcd. for C₁₀H₁₈N (MH⁺) 152.1439, found152.1435.

(xvi) 2-Amino-1,2-diphenylpent-4-en-1-ol (6p)

6p was isolated as a clear, colorless crystalline solid. Thediastereomeric ratio (d.r.=88:12) was determined by ¹H NMR of the crudesample. Main diastereomer: m.p.=85-86° C. (CH₂Cl₂); ¹H NMR (CDCl₃, 300MHz) δ 7.30-7.06 (8H, m), 6.90-6.85 (2H, m), 5.56-5.40 (1H, m), 5.12(1H, d, J=17.0 Hz), 5.00 (1H, d, J=10.0 Hz), 4.74 (1H, s), 2.95 (1H, dd,J=14.0, 5.5 Hz), 2.65 (1H, dd, J=14.0, 9.0 Hz), 2.08 (3H, br s); ¹³C NMR(CDCl₃, 75 MHz) δ142.54, 140.02, 133.74, 127.62, 127.42, 127.24, 127.10,126.71, 126.50, 118.96, 79.91, 61.70, 43.45; IR (film)

3422, 1638 cm⁻¹; HRMS (Cl) m/z calcd. for C₁₇H₂₀NO (MH⁺) 254.1545, found254.1543.

(xvii)(1S*,2R*,5R*)-2-Allyl-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-ylamine(6q)

6q was isolated as a clear, colorless oil (d.r.=97:3). Thediastereomeric ratio was determined by ¹H NMR of the crude sample. ¹HNMR (CDCl₃, 300 MHz) δ 5.85 (1H, ddt, J=17.5, 10.5, 7.5 Hz), 5.13-5.02(3H, m), 2.36 (1H, dt, J=9.0, 5.5 Hz), 2.20 (1H, dd, J=13.5, 7.0 Hz),2.13 (1H, dd, J=13.5, 8.0 Hz), 1.98-1.88 (2H, m), 1.68 (3H, d, J=1.5Hz), 1.60-1.35 (3H, m), 1.33 (3H, s), 1.05 (3H, s); ¹³C NMR (CDCl₃, 75MHz) δ 143.51, 133.89, 124.42, 118.23, 57.24, 52.84, 47.64, 45.88,41.87, 33.78, 27.36, 23.85, 22.77; IR (film)

3410, 1713, 1681, 1623 cm⁻¹; HRMS (ESI) m/z calcd. for C₁₃H₂₂N (MH⁺)192.1752, found 192.1756.

Example 2 Results for the Allylation of N-Unsubstituted Imines Derivedfrom Ketones

The allylboron class of reagents were demonstrably superior in terms ofreactivity and chemoselectivity [W. R. Roush, in Houben-Weyl,Stereoselective Synthesis, ed. G. Helmchen, R. W. Hoffmann, J. Mulzerand E. Schaumann, Georg Thieme Verlag, Stuttgart, 1995, vol. E21b, pp1410-1486; D. S. Matteson, in Stereodirected Synthesis withOrganoboranes, Springer-Verlag, Berlin, 1995]. In order to ascertain thereagent of choice, the present inventors have investigated the additionof a range of allylboron compounds to N-unsubstituted ketimines whichare derived from ketones. The results are shown in Table 1. As can beseen from the Table, the more reactive allylboron reagents, 5d and 5e[H. C. Brown, U.S. Racherla and P. J. Pellechia, J. Org. Chem., 1990,55, 1868] displayed the highest efficacy in terms of isolated yields ofhomollylic amine 6a (entries 4 and 5). A major issue of concern in allthese reactions—chemoselectivity of imine versus ketone addition—wasaddressed by analyzing the organic extracts from the acid-base workup of6a (entries 4, 5). It was determined that the corresponding homoallylicalcohol of 6a was formed in minor amounts (≦5%).

Due to the ease of the preparation of the allylboron reagent 5e and thesimple purification of the resulting products, the present inventorshave further investigated a series of ketones with reagent 5e inmethanolic ammonia (Table 2). Aliphatic (entries 1-4), electron richaromatic (entry 5), electron deficient aromatic (entries 6 and 7),α,β-unsaturated (entry 8), cyclic (entries 9 and 10) andheterocyclic-substituted (entries 11 and 12) ketones were successfullyallylated under the standard conditions. The resulting homoallylicamines (6) were easily isolated in high yields through simple acid-baseextraction, and in all cases but one, did not require any furtherpurification. A variety of functional groups were also found to betolerated in the reaction sequence including the nitro (entry 7), cyano(entry 6), unprotected hydroxy (entry 2) and amino groups (entry 12).

Still further, the present inventors have expanded the scope of thestudy to include the allylation of ketones containing a pre-existingstereocenter. The substrates (1n-q) were subjected to the standard setof reaction and work-up conditions, the results of which are shown inTable 3. Good to excellent yields of tertiary carbinamines 6n-q wereobtained in all cases, while the observed diastereoselectivities, asdetermined by ¹H NMR, varied from modest for the reaction of4-tert-butylcyclohexanone, norchamphor, and benzoin (equations 1, 2 and3 respectively) to excellent for verbenone (equation 4).

Example 3 General Procedure for the Crotylation of N-UnsubstitutedImines Derived from Ketones

The protocol for the allylation of N-unsubstituted imines derived fromketones was followed with the exception that the boron reagent waschanged to either either (E)- or (Z)-crotylboronic acid (2M in MeOH, 0.5mL, 1.00 mmol).

(i) (1S*,2S*)-1,2-Dimethyl-1-(4-trifluoromethylphenyl)but-3-enylamine(4a)

4a was isolated as a clear, colorless oil (d.r.=97:3). Thediastereomeric ratio was determined by ¹H NMR of the crude sample. ¹HNMR (CDCl₃, 300 MHz) δ 7.60 (2H, d, J=9.0 Hz), 7.56 (2H, d, J=9.0 Hz),5.66-5.53 (1H, m), 5.10-5.00 (2H, m), 2.53 (1H, pentet, J=7.0 Hz), 1.49(2H, br s), 1.46 (3H, s), 0.91 (3H, d, J=7.0 Hz); ¹³C NMR (CDCl₃, 75MHz) δ 152.45, 139.63, 128.52 (q, J=30 Hz), 126.37, 124.79 (q, J=3.5Hz), 124.64 (q, J=270 Hz), 116.45, 55.96, 48.82, 27.13, 14.30; IR (film)

3378, 1636 cm⁻¹; HRMS (ESI) m/z calcd. for C₁₃H₁₇F₃N (MH⁺) 244.1313,found 244.1305.

(ii) (1S*,2R*)-1,2-Dimethyl-1-(4-trifluoromethylphenyl)but-3-enylamine(4b)

4b was isolated as a clear, colorless oil (d.r.=96:4). Thediastereomeric ratio was determined by ¹H NMR of the crude sample. ¹HNMR (CDCl₃, 300 MHz) δ 7.56 (4H, apparent s), 5.75 (1H, ddd, J=18.5,10.5, 8.0 Hz), 5.13-5.03 (2H, m), 2.53 (1H, pentet, J=7.5 Hz), 1.58 (2H,br s), 1.43 (3H, s), 0.78 (3H, d, J=7.5 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ152.10, 139.46, 128.02 (q, J=30 Hz), 126.23, 125.83 (q, J=270 Hz),124.73 (q, J=3.5 Hz), 116.34, 55.56, 48.65, 29.51, 14.51; IR (film)ν3390, 1637 cm⁻¹; HRMS (ESI) m/z calcd. for C₁₃H₁₇F₃N (MH⁺) 244.1313,found 244.1304.

(iii) (2S*,3S*)-2-Amino-3-methyl-2-phenylpent-4-enoic acid amide (4c)

4c was isolated as a clear, colorless, crystalline solid (d.r.=97:3):m.p=90° C. (CH₂Cl₂); ¹H NMR (CDCl₃, 300 MHz) δ 7.65-7.58 (2H, m),7.35-7.18 (4H, m), 6.20 (1H, brs), 5.46 (1H, ddd, J=17.5, 10.0, 6.5 Hz),5.05-4.95 (2H, m), 3.59 (1H, pentet, J=6.5 Hz), 1.59 (2H, br s), 1.08(3H, d, J=6.5 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 176.99, 141.60, 138.23,128.16, 127.04, 125.64, 116.69, 65.54, 42.58, 12.27; IR (film) ν3441,3207, 1710, 1620, 1637 cm⁻¹; HRMS (Cl) m/z calcd. for C₁₁H₁₇N₂O (MH⁺)205.1341, found 205.1332.

(iv) (2S*,3R*)-2-Amino-3-methyl-2-phenylpent-4-enoic acid amide (4d)

4d was isolated as a clear, colorless, crystalline solid (d.r.=96:4):m.p=136° C. (CH₂Cl₂); ¹H NMR (CDCl₃, 500 MHz) δ 7.64-7.60 (2H, m),7.35-7.24 (4H, m), 6.02 (1H, ddd, J=17.5, 10.5, 5.0 Hz), 5.59 (1H, brs), 5.26 (1H, dt, J=10.5, 1.5 Hz), 5.17 (1H, dt, J=17.5, 1.5 Hz),3.76-3.69 (1H, m), 1.63 (2H, br s), 0.73 (3H, d, J=7.0 Hz); ¹³C NMR(CDCl₃, 125 MHz) δ 177.15, 141.16, 139.07, 128.24, 127.06, 125.54,117.21, 65.47, 41.87, 10.97; IR (film) ν3432, 3170, 1715, 1633 cm⁻¹;HRMS (Cl) m/z calcd. for C₁₁H₁₇N₂O (MH⁺) 205.1341, found 205.1337.

(v) (1S*,2S*)-1,2-Dimethyl-1-phenylbut-3-enylamine (4e)

4e was isolated as a clear, colorless oil (d.r.=97:3). Thediastereomeric ratio was determined by ¹H NMR of the crude sample. ¹HNMR (CDCl₃, 300 MHz) δ 7.42-7.10 (4H, m), 5.65-5.55 (1H, m), 4.96-5.02(2H, m), 2.45 (1H, dq, J=7.0 Hz), 1.50 (2H, br s), 1.38 (3H, s), 0.83(3H, d, J=7.0 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 148.22, 140.30, 127.87,126.13, 125.79, 115.90, 56.81, 49.02, 26.68, 14.49 [C. Ogawa, M. Sugiuraand S. Kobayashi, J. Org. Chem., 2002, 67, 5359].

(vi) 2-Amino-2,3-dimethylpent-4-enoicacid amide (4f)

4f was isolated as a clear, colorless oil (d.r.=60:40). Thediastereomeric ratio was determined by ¹H NMR of the crude sample. Maindiastereomer: ¹H NMR (CDCl₃, 300 MHz) δ 7.41 (1H, br s), 5.95-5.60 (2H,m), 5.15-5.05 (2H, m), 2.81 (1H, pentet, J=6.5 Hz), 1.28 (3H, s), 1.26(2H, br s), 0.99 (3H, d, J=6.5 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 180.06,139.33, 116.28, 59.62, 43.29, 25.10, 11.88; IR (film) ν3444, 3250, 1691,1654, 1557 cm⁻¹; HRMS (Cl) m/z calcd. for C₇H₁₄N₂O (MH⁺) 143.1184, found143.1186.

Example 4 Results for the Crotylation of N-Unsubstituted Imines Derivedfrom Ketones

The crotylation of a select number of ketones was examined under aslightly modified set of conditions (2.0 equiv of 5e, 10 equiv. of NH₃,rt, 24 h) (Table 4). Excellent diastereoselectivities were obtained withacetophenone derivatives (entries 1-4). The anti diastereomer (4a/c) wasformed when (E)-crotylboronic acid (7a) was employed as the reagent,while (Z)-crotylboronic acid (7b) afforded the syn diastereomer (4b/d).The stereochemistry of the crotylated products 4 were assigned basedupon the reaction of 7a with acetophenone (entry 5) which afforded thepreviously known anti diastereomer 4e in moderate yield and excellentdiastereoselectivity (d.r.=97:3) [C. Ogawa, M. Sugiura and S. Kobayashi,J. Org. Chem., 2002, 67, 5359]. Crotylation of methyl pyruvate (entry6), on the other hand, was not diastereoselective likely due to thesimilar steric sizes of the methyl and methylformate groups. The resultsfrom entries 3-5 also constitute a convenient route to α-allylated aminoacid derivatives.

While the present invention has been described with reference to whatare presently considered to be the preferred examples, it is to beunderstood that the invention is not limited to the disclosed examples.To the contrary, the invention is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

All publications, patents and patent applications are hereinincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety. Where a term in the present application is found to bedefined differently in a document incorporated herein by reference, thedefinition provided herein is to serve as the definition for the term.

TABLE 1 Addition of allyl boron reagents (5) to N-unsubstituted ketiminederived from 1a.

Yield of 6a Entry 5 (%)^(a) 1

35 2

29 3

43 4

 70^(b,c) 5

 79^(b) ^(a)Isolated yield after acid-base extraction. ^(b)Analysis (¹HNMR, 2.4,6-trimethylbenzene standard) of the organic phase from theacid-base work-up revealed ≦5% of the corresponding homoallylic alcohol.^(c)Isolated yield after acid-base extraction and preparative TLC.

TABLE 2 Reaction of N-unsubstituted imines derived from ketones withallylboronic acid (5e)^(a).

Entry Ketone Yield (%)^(b) 1 Et₂C═O (1b) 73 (6b) 2

(1c) 80 (6c) 3

(1d) 78 (6d) 4

(1e) 85 (6e) 5 4-MeOC₆H₄C(O)CH₂CH₃ (1f) 72 (6f) 6 4-NCC₆H₄C(O)CH₃ (1g)80 (6g) 7 4-O₂NC₆H₄C(O)CH₃ (1h) 87 (6h) 8

(1i)  70 (6i)^(c) 9

(1j) 78 (6j) 10

(1k) 92 (6k) 11

(1l) 75 (6l) 12

(1m) 80 (6m) ^(a)Standard reaction conditions: A solution of the ketone(0.5 mmol), ammonia (ca. 7N in MeOH, 0.75 mL, ca. 10 equiv.) andallylboronic acid (5e) (2M in MeOH, 0.40 mL, 0.80 mmol) was stirred for16 h at rt. ^(b)Isolated yield after acid-base extraction. ^(c)Isolatedyield after acid-base extraction, and preparative TLC.

TABLE 3 Reaction of N-unsubstituted imines derived from ketones withallylboronic acid (5e) in which the ketones contain a pre-existingstereocentre.

TABLE 4 Reaction of N-unsubstituted ketimines with (E)- and(Z)-crotylboronic acid (7a/b)^(a)

Crotyl Yield Entry reagent Product (%)^(b) d.r. 1 7a

80 (4a) 97:3 2 7b

73 (4b)^(c) 96:4 3 7a

95 (4c)^(d) 97:3 4 7b

92 (4d)^(d) 96:4 5 7a

50 (4e) 97:3 6 7a

88 (4f)^(e) 60:40 ^(a)Standard reaction conditions: ketone (0.5 mmol),ammonia (ca. 7N in MeOH, 0.75 mL, ca. 10 equiv.) and crotylboronic acid(7a/b) (2M in MeOH, 0.50 mL, 1.00 mmol) were stirred for 24 h at rt.^(b)Isolated yield after acid-base extraction. ^(c)Isolated yield afteracid-base extraction, and preparative TLC. ^(d)Methyl benzoylformate wasemployed as the starting ketone, and aminolysis of the ester wasobserved. ^(e)Methylpyruvate was employed as the starting ketone, andaminolysis of the ester was observed.

1. A method of preparing an amine of the formula Ia and/or Ib comprisingreacting a compound of formula II with a compound of formula III:

wherein R¹ and R² are independently selected from C₁₋₂₀alkyl,C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₃₋₂₀cycloalkyl, C₃₋₂₀cycloalkoxy, aryl,aryloxy, heteroaryl and heteroaryloxy, all of which are optionallysubstituted and one or more of the carbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy,C₂₋₂₀alkenyl, C₃₋₂₀cycloalkyl and C₃₋₂₀cycloalkoxy, is optionallyreplaced with a heteromoiety selected from 0, S, N, NR¹⁰ and NR¹⁰R¹¹; orR¹ and R² are linked to form an optionally substituted monocyclic orpolycyclic ring system having 4 to 20 atoms including the carbonyl towhich R¹ and R² are bonded, and one or more of the carbons of the ringsystem is optionally replaced with a heteromoiety selected from O, S, N,NR¹⁰ and NR¹⁰R¹¹; R³ to R⁷ are independently selected from H,C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₃₋₂₀cycloalkyl,C₃₋₂₀cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, thelatter 9 groups being optionally substituted and one or more of thecarbons in C₁₋₂₀alkyl, C₁₋₂₀alkoxy, C₂₋₂₀alkenyl, C₃₋₂₀cycloalkyl andC₃₋₂₀cycloalkoxy, is optionally replaced with a heteromoiety selectedfrom O, S, N, NR¹⁰ and NR¹⁰R¹¹; R⁸ and R⁹ are independently selectedfrom H, C₁₋₂₀alkyl, C₃₋₂₀cycloalkyl, aryl and heteroaryl, the latter 4groups being optionally substituted; or R⁸ and R⁹ are linked to form anoptionally substituted monocyclic or polycyclic ring system having 4 to20 atoms, including the B and O atoms to which R⁸ and R⁹ are bonded; R¹⁰and R¹¹ are independently selected from H, C₁₋₂₀alkyl, C₃₋₂₀cycloalkyl,aryl and heteroaryl, the latter 4 groups being optionally substituted,in the presence of ammonia NH₃ or an ammonia equivalent of the formulaNH₄ ⁺X⁻, wherein X is an anionic ligand, wherein the amine of theformula Ia and/or Ib is produced in a yield of 50% or more.
 2. Themethod according to claim 1, wherein R¹ and R² in the compounds of theformulae Ia, Ib and II are independently selected from C₁₋₁₀alkyl,C₂₋₁₀alkenyl, aryl and heteroaryl, all of which being optionallysubstituted; or R¹ and R² are linked to form an optionally substitutedmonocyclic or polycyclic ring system having 6 to 16 carbons includingthe carbonyl to which R¹ and R² are bonded and one or more of thecarbons of the ring system is optionally replaced with a heteromoietyselected from O, S, N, NR¹⁰ and NR¹⁰R¹¹, in which R¹⁰ and R¹¹ areindependently selected from H, C₁₋₆alkyl and aryl.
 3. The methodaccording to claim 2, wherein R¹ and R² in the compounds of the formulaeIa, Ib and II are independently selected from methyl, ethyl, propyl,butyl, pentyl, ethene, styrene, phenyl, benzyl, thiophene and indole,all of which are optionally substituted.
 4. The method according toclaim 1, wherein R¹ and R² in the compounds of the formulae Ia, Ib andII are linked to form a ring system selected from cyclohexane,bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene and fluorene, all ofwhich are optionally substituted, and one or more of the carbons ofcyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene or fluoreneis optionally replaced with a heteromoiety selected from O, S, N andNR¹⁰; in which R¹⁰ is H or benzyl.
 5. The method according to claim 1,wherein the optional substituents on R¹ and R² in the compounds of theformulae Ia, Ib and II are independently selected from OH, halo, CN,NO₂, phenyl, benzyl, OC₁₋₆alkoxy, C₁₋₆alkyl, C₁₋₆alkenyl,C₁₋₆alkenyloxy, NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl),C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl, andSC₁₋₄alkyl.
 6. The method according to claim 5, wherein the optionalsubstituents on R¹ and R² in the compounds of the formulae Ia, Ib and IIare independently selected from OH, F, Cl, Br, CN, NO₂, phenyl andC₁₋₄alkyl.
 7. The method according to claim 1, wherein the optionalsubstituents on R¹ and R² in the compounds of the formulae Ia, Ib and IIfurther comprise at least one stereocenter.
 8. The method according toclaim 1, wherein R³ to R⁷ in the compounds of the formulae Ia, Ib andIII are independently selected from H, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, aryland heteroaryl, the latter 4 groups being optionally substituted and oneor more of the carbons in C₁₋₁₀alkyl and C₃₋₁₀cycloalkyl is optionallyreplaced with a heteromoiety selected from O, S, N, NR¹⁰ and NR¹⁰R¹¹ inwhich R¹⁰ and R¹¹ are independently selected from H and C₁₋₆alkyl. 9.The method according to claim 8, wherein R³ to R⁷ in the compounds ofthe formulae Ia, Ib and III are independently selected from H andC₁₋₆alkyl.
 10. The method according to claim 9, wherein R³ to R⁷ in thecompounds of the formulae Ia, Ib and III are independently selected fromH and methyl.
 11. The method according to claim 1, wherein the optionalsubstituents on R³ and R⁷ in the compounds of the formulae Ia, Ib andIII are independently selected from OH, halo, CN, NO₂, phenyl, benzyl,OC₁₋₆alkoxy, C₁₋₆alkenyl, C₁₋₆alkenyloxy, NH₂, NH(C₁₋₆alkyl),N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl,SO₂NH₂, SO₂NHC₁₋₆alkyl, and SC₁₋₄alkyl.
 12. The method according toclaim 1, wherein R⁸ and R⁹ in the compound of the formula III areindependently selected from H, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, aryl andheteroaryl, the latter 4 groups being optionally substituted; or R⁸ andR⁹ in the compound of the formula III are linked to form an optionallysubstituted monocyclic or polycyclic ring system having 5 to 12 atoms,including the B and O atoms to which R⁸ and R⁹ are bonded.
 13. Themethod according to claim 12, wherein R⁸ and R⁹ in the compound of theformula III are independently selected from H or C₁₋₆alkyl; or R⁸ and R⁹in the compound of the formula III are linked to form an optionallysubstituted monocyclic or bicyclic ring system having 5 to 12 atoms,including the B and O atoms to which R⁸ and R⁹ are bonded.
 14. Themethod according to claim 1, wherein the optional substituents on R⁸ andR⁹ in the compound of the formula III are independently selected fromOH, halo, CN, NO₂, phenyl, benzyl, OC₁₋₆alkoxy, C₁₋₆alkyl, C₁₋₆alkenyl,C₁₋₆alkenyloxy, NH₂, NH(C₁₋₆alkyl), N(C₁₋₆alkyl)(C₁₋₆alkyl),C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl, SO₂NH₂, SO₂NHC₁₋₆alkyl, andSC₁₋₄alkyl.
 15. The method according to claim 14, wherein the optionalsubstituent on R⁸ and R⁹ in the compound of the formula III isC₁₋₄alkyl.
 16. The method according to claim 1, wherein X is selectedfrom halo, R¹²COO, R¹²SO₄ and BF₄ in which R¹² is selected fromC₁₋₁₀alkyl, C₃₋₂₀cycloalkyl, aryl and heteroaryl, all of which areoptionally substituted; and wherein the optional substituents areindependently selected from OH, halo, CN, NO₂, phenyl, benzyl,OC₁₋₆alkoxy, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkenyloxy, NH₂, NH(C₁₋₆alkyl),N(C₁₋₆alkyl)(C₁₋₆alkyl), C(O)C₁₋₆alkyl, C(O)OC₁₋₆alkyl, SO₂C₁₋₆alkyl,SO₂NH₂, SO₂NHC₁₋₆alkyl, and SC₁₋₄alkyl.
 17. The method according toclaim 1, wherein the method is performed in the presence of ammonia. 18.The method according to claim 1, wherein the method is performed in anorganic solvent.
 19. The method according to claim 18, wherein theorganic solvent is selected from methanol, ethanol, propanol, butanol,toluene, tetrahydrofuran, acetonitrile, benzene and methylene chloride.20. The method according to claim 19, wherein the organic solvent ismethanol.
 21. The method according to claim 1, wherein the method isperformed at a temperature of from −40° C. to +100° C.
 22. The methodaccording to claim 21, wherein the method is performed at roomtemperature.